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Acetazolamide for Treating NPH in Shunt-candidates Patients

Primary Purpose

Normal Pressure Hydrocephalus

Status
Unknown status
Phase
Phase 2
Locations
Israel
Study Type
Interventional
Intervention
Acetazolamide
Sponsored by
Rabin Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Normal Pressure Hydrocephalus focused on measuring NPH, Acetazolamide

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Included will be subjects with a probable diagnosis of NPH. The diagnosis will be based primarily on presence of gait impairment plus at least one other impairment in urinary symptoms, cognition impairment or both.

  1. Are 50 years old or older.
  2. Patients who meet the criteria for NPH based on:

    • A typical personal history.
    • A typical brain imaging on head CT or MRI.
    • Normal lumbar puncture findings excluding other conditions.
    • Exclusion of other more likely diagnosis.
  3. Patients who underwent large-volume spinal tap and subsequently improved clinically by at least 10% in gait function or cognition.

Exclusion Criteria:

  • Cirrhosis or marked liver disease or dysfunction.
  • Severe renal disease or dysfunction.
  • Acidosis.
  • Hypersensitivity to acetazolamide, sulfonamides, or any component of the formulation.
  • Decreased sodium and/or potassium levels.
  • Adrenocortical insufficiency.
  • Patients with cognitive impairment who will not be able to give informed consent.

Sites / Locations

  • Rabin Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

treatment group

Arm Description

patients who met the inclusion criteria will be allocated to the treatment group, and will receive acetazolamide from time of diagnosis until shunt surgery (2-6 weeks).

Outcomes

Primary Outcome Measures

Change from Baseline Gait
Change from Baseline gait will be evaluated by the neurosurgery department's physiotherapist, using the timed-up-and-go (TUG) test (measured in seconds, higher values represent a worse outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later).
Change from Baseline Balance
Change from Baseline balance will be evaluated by the neurosurgery department's physiotherapist, using the TINETTI balance assessment score. (0-28 scale, higher values represent a better outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later).

Secondary Outcome Measures

Change from Baseline concentration function
concentration function will be evaluated by the neurosurgery department's neuropsychologist using the color trial test (seconds, higher values represent a worse outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later).
Change from Baseline visuospatial function
visuospatial function will be evaluated by the neurosurgery department's neuropsychologist using the clock drawing test (0-10 scale, higher values represent a better outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later).
Change from Baseline verbal fluency
verbal fluency will be evaluated by the neurosurgery department's neuropsychologist using the verbal fluency test (Controlled Oral Word Association Test, number of words in one minute, higher values represent a better outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later).

Full Information

First Posted
December 10, 2018
Last Updated
December 17, 2018
Sponsor
Rabin Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03779594
Brief Title
Acetazolamide for Treating NPH in Shunt-candidates Patients
Official Title
Acetazolamide for Treating NPH in Shunt-candidates Patients: an Open Label Feasibility Trial
Study Type
Interventional

2. Study Status

Record Verification Date
December 2018
Overall Recruitment Status
Unknown status
Study Start Date
December 2018 (Anticipated)
Primary Completion Date
December 2019 (Anticipated)
Study Completion Date
December 2019 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Rabin Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Normal pressure hydrocephalus (NPH) consists of a triad of gait disturbance, cognitive deterioration, and urinary incontinence and is characterized by enlarged cerebral ventricles. Current treatment recommendations are based on surgical diversion of Cerebrospinal fluid (CSF), by a ventriculoperitoneal shunt. When patients are appropriately selected, shunting for NPH has a sustained effect in one-half to two-thirds of patients with a reasonable complication rate. However, evidence regarding the efficacy of shunt surgery consists largely of observational studies with relatively short-term follow-up. With regards to the adverse effects of shunting, even though decreased substantially in recent years, shunt complications are still common. Recent studies report ten to twenty-two percent of serious adverse effects following shunt surgery, mainly subdural hematoma (SDH) requiring surgery, infection, and cerebral infarction or hemorrhage. Most complication occur in the first year after the procedure. Many others suffer from adverse events that considered non-serious, such as postural headache and asymptomatic SDH. Since shunt complications are common and potentially severe, there is a need for a better way to identify those patients that will likely benefit from shunting, and find alternative treatments for those unwilling or unable to withstand surgery. Acetazolamide has been shown to reduce the production of CSF in clinical cases of raised intracranial pressure. It is considered the drug of choice for the treatment of idiopathic intracranial hypertension (pseudotumor cerebri). Intuitively, acetazolamide can be effective for the treatment of NPH by reducing the volume of CSF in the brain, and serve as a medical alternative to shunting. Few case reports and small series demonstrated improvement in MRI abnormalities in NPH-patients after administrating the medication. This open-label study will examine the feasibility and effectiveness of acetazolamide in NPH-diagnosed patients who are shunt-candidates. Patients will be treated from time of diagnosis, and gait and cognition will be evaluated after 2-6 weeks. This trial would possibly pave the way to a larger randomized placebo-controlled trials, and perhaps offer a medical alternative to surgery for elderly patients and for patients for which operation is contraindicated.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Normal Pressure Hydrocephalus
Keywords
NPH, Acetazolamide

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
treatment group
Arm Type
Experimental
Arm Description
patients who met the inclusion criteria will be allocated to the treatment group, and will receive acetazolamide from time of diagnosis until shunt surgery (2-6 weeks).
Intervention Type
Drug
Intervention Name(s)
Acetazolamide
Other Intervention Name(s)
Diamox
Intervention Description
Patients will be assign and treated by acetazolamide from time of allocation until surgery (2-6 weeks after treatment initiation). The maximal dose of acetazolamide will be the same dose used to treat glaucoma, considering similarity of patients' characteristics, such as age and polypharmacy. We will start at a low dose of 250 mg once a day, and increase it slowly to a maximal dose of 500 mg twice a day. Dose will be individualized according to side-effects and tolerability. Renal and liver function tests will be performed before initiation of treatment, and will be examined again two weeks after treatment had begun.
Primary Outcome Measure Information:
Title
Change from Baseline Gait
Description
Change from Baseline gait will be evaluated by the neurosurgery department's physiotherapist, using the timed-up-and-go (TUG) test (measured in seconds, higher values represent a worse outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later).
Time Frame
Baseline, week 4
Title
Change from Baseline Balance
Description
Change from Baseline balance will be evaluated by the neurosurgery department's physiotherapist, using the TINETTI balance assessment score. (0-28 scale, higher values represent a better outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later).
Time Frame
Baseline, week 4
Secondary Outcome Measure Information:
Title
Change from Baseline concentration function
Description
concentration function will be evaluated by the neurosurgery department's neuropsychologist using the color trial test (seconds, higher values represent a worse outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later).
Time Frame
Baseline, week 4
Title
Change from Baseline visuospatial function
Description
visuospatial function will be evaluated by the neurosurgery department's neuropsychologist using the clock drawing test (0-10 scale, higher values represent a better outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later).
Time Frame
Baseline, week 4
Title
Change from Baseline verbal fluency
Description
verbal fluency will be evaluated by the neurosurgery department's neuropsychologist using the verbal fluency test (Controlled Oral Word Association Test, number of words in one minute, higher values represent a better outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later).
Time Frame
Baseline, week 4
Other Pre-specified Outcome Measures:
Title
adverse effects
Description
All adverse effects that may be attributed to the treatment will be recorded
Time Frame
week 2-6

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Included will be subjects with a probable diagnosis of NPH. The diagnosis will be based primarily on presence of gait impairment plus at least one other impairment in urinary symptoms, cognition impairment or both. Are 50 years old or older. Patients who meet the criteria for NPH based on: A typical personal history. A typical brain imaging on head CT or MRI. Normal lumbar puncture findings excluding other conditions. Exclusion of other more likely diagnosis. Patients who underwent large-volume spinal tap and subsequently improved clinically by at least 10% in gait function or cognition. Exclusion Criteria: Cirrhosis or marked liver disease or dysfunction. Severe renal disease or dysfunction. Acidosis. Hypersensitivity to acetazolamide, sulfonamides, or any component of the formulation. Decreased sodium and/or potassium levels. Adrenocortical insufficiency. Patients with cognitive impairment who will not be able to give informed consent.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Gilad Kenan, MD
Phone
97289779181
Email
giladankori@gmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Yosi Laviv, MD
Email
YossiL2@clalit.org.il
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yosi Laviv, MD
Organizational Affiliation
Rabin Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Rabin Medical Center
City
Petah Tikva
ZIP/Postal Code
49100
Country
Israel
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gilad Kenan, MD
Phone
528457654
Email
giladankori@gmail.com
First Name & Middle Initial & Last Name & Degree
Yosi Laviv, MD
First Name & Middle Initial & Last Name & Degree
Idan Levitan, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
24682964
Citation
Jaraj D, Rabiei K, Marlow T, Jensen C, Skoog I, Wikkelso C. Prevalence of idiopathic normal-pressure hydrocephalus. Neurology. 2014 Apr 22;82(16):1449-54. doi: 10.1212/WNL.0000000000000342. Epub 2014 Mar 28.
Results Reference
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PubMed Identifier
28293475
Citation
Kuriyama N, Miyajima M, Nakajima M, Kurosawa M, Fukushima W, Watanabe Y, Ozaki E, Hirota Y, Tamakoshi A, Mori E, Kato T, Tokuda T, Urae A, Arai H. Nationwide hospital-based survey of idiopathic normal pressure hydrocephalus in Japan: Epidemiological and clinical characteristics. Brain Behav. 2017 Jan 27;7(3):e00635. doi: 10.1002/brb3.635. eCollection 2017 Mar.
Results Reference
background
PubMed Identifier
26644048
Citation
Halperin JJ, Kurlan R, Schwalb JM, Cusimano MD, Gronseth G, Gloss D. Practice guideline: Idiopathic normal pressure hydrocephalus: Response to shunting and predictors of response: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2015 Dec 8;85(23):2063-71. doi: 10.1212/WNL.0000000000002193. Erratum In: Neurology. 2016 Feb 23;86(8):793.
Results Reference
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PubMed Identifier
21849644
Citation
Klassen BT, Ahlskog JE. Normal pressure hydrocephalus: how often does the diagnosis hold water? Neurology. 2011 Sep 20;77(12):1119-25. doi: 10.1212/WNL.0b013e31822f02f5. Epub 2011 Aug 17.
Results Reference
background
PubMed Identifier
12137677
Citation
Esmonde T, Cooke S. Shunting for normal pressure hydrocephalus (NPH). Cochrane Database Syst Rev. 2002;2002(3):CD003157. doi: 10.1002/14651858.CD003157.
Results Reference
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PubMed Identifier
21235310
Citation
Tisell M, Tullberg M, Hellstrom P, Edsbagge M, Hogfeldt M, Wikkelso C. Shunt surgery in patients with hydrocephalus and white matter changes. J Neurosurg. 2011 May;114(5):1432-8. doi: 10.3171/2010.11.JNS10967. Epub 2011 Jan 14.
Results Reference
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PubMed Identifier
25934242
Citation
Kazui H, Miyajima M, Mori E, Ishikawa M; SINPHONI-2 Investigators. Lumboperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (SINPHONI-2): an open-label randomised trial. Lancet Neurol. 2015 Jun;14(6):585-94. doi: 10.1016/S1474-4422(15)00046-0. Epub 2015 Apr 28.
Results Reference
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PubMed Identifier
23975646
Citation
Toma AK, Papadopoulos MC, Stapleton S, Kitchen ND, Watkins LD. Systematic review of the outcome of shunt surgery in idiopathic normal-pressure hydrocephalus. Acta Neurochir (Wien). 2013 Oct;155(10):1977-80. doi: 10.1007/s00701-013-1835-5. Epub 2013 Aug 23.
Results Reference
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PubMed Identifier
26587993
Citation
ten Hove MW, Friedman DI, Patel AD, Irrcher I, Wall M, McDermott MP; NORDIC Idiopathic Intracranial Hypertension Study Group. Safety and Tolerability of Acetazolamide in the Idiopathic Intracranial Hypertension Treatment Trial. J Neuroophthalmol. 2016 Mar;36(1):13-9. doi: 10.1097/WNO.0000000000000322.
Results Reference
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PubMed Identifier
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Citation
Alperin N, Oliu CJ, Bagci AM, Lee SH, Kovanlikaya I, Adams D, Katzen H, Ivkovic M, Heier L, Relkin N. Low-dose acetazolamide reverses periventricular white matter hyperintensities in iNPH. Neurology. 2014 Apr 15;82(15):1347-51. doi: 10.1212/WNL.0000000000000313. Epub 2014 Mar 14.
Results Reference
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Citation
Ivkovic M, Reiss-Zimmermann M, Katzen H, Preuss M, Kovanlikaya I, Heier L, Alperin N, Hoffmann KT, Relkin N. MRI assessment of the effects of acetazolamide and external lumbar drainage in idiopathic normal pressure hydrocephalus. Fluids Barriers CNS. 2015 Apr 2;12:9. doi: 10.1186/s12987-015-0004-z.
Results Reference
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Acetazolamide for Treating NPH in Shunt-candidates Patients

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